tbuckley/cabot-search huggingface dataset:
Abstract 3812: Circular RNAs from the PAX5 oncogene are overexpressed in B-cell malignancies and modulate cancer processes
Authors: Danick M. Martin, Brandon Hannay, Alexis Martin, Vanessa Veilleux, Nicholas Finn, Gilles A. Robichaud
Journal: Cancer Research (2023)

Abstract Circular RNAs (circRNAs) represent a new class of gene products involved in many biological processes. Due to their ability to bind and modulate co-interacting proteins and microRNAs (miRs), circRNAs represent new signaling mediators in cell biology and cancer processes. Recently, we identified circRNAs from the PAX5 oncogene (circPAX5) in B-cells. Given that PAX5 gene products are well established as potent oncogenic regulators of B-cell cancer lesions, we hypothesized that circPAX5 may also be potentially involved in pathogenic processes of B-cell malignancies. In this study, we wanted to understand the role of circPAX5 in B-cell cancer processes and elucidate new potential targets for diagnostic and therapeutic avenues. Using a series of B-cell cancer models and clinical samples, we sequenced, mapped, and profiled circPAX5 expression profiles and found that circPAX5 products are indeed overexpressed in various cancer cell types where the predominant expressed isoform consisted of exons 2 to 5 (circPAX5_2-5) of the PAX5 locus. In addition, we isolated circPAX5 complexes from cancer cells and identified co-interacting small non-coding RNAs, notably microARNs (miRs) by deep sequencing. To further elucidate the functional role of circPAX5 and miR co-interactions, selected miRs from the list were then conditionally overexpressed in B-cells followed by cellular phenotypic assays. Altogether, our results characterize new signaling products and pathways in B-cells. Our data also suggests that circPAX5 products are involved in B-cell cancer processes and could potentially represent new cancer pathways targeted for strategic therapeutic and/or diagnostic strategies in B-cell cancer lesions Citation Format: Danick M. Martin, Brandon Hannay, Alexis Martin, Vanessa Veilleux, Nicholas Finn, Gilles A. Robichaud. Circular RNAs from the PAX5 oncogene are overexpressed in B-cell malignancies and modulate cancer processes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3812.
Abstract 2287: Circulating extracellular vesicles from patients with advanced pancreatic cancer contain low levels of tumor-derived DNA
Authors: Morten Lapin, Kjersti Tjensvoll, Karoline Nedrebø, Eline Taksdal, Hans Janssen, Bjørnar Gilje, Oddmund Nordgard
Journal: Cancer Research (2023)

Abstract Purpose: Extracellular vesicles (EVs) have been shown to contain nucleic acids, including DNA. Several studies have highlighted the potential of EV-derived DNA (evDNA) as a circulating biomarker, even demonstrating that evDNA can outperform circulating cell-free DNA (cfDNA) in terms of sensitivity. Here, we evaluated whether EVs could be a potential source of tumor-derived DNA in patients with advanced pancreatic cancer. Methods: evDNA from both DNase-treated and untreated circulating EVs, enriched from patients with advanced pancreatic cancer (n=10), was analyzed by fluorometry and digital droplet PCR to determine the level of evDNA inside and outside (surface-bound) the EVs. To also determine if choice of methodology affected the results, EVs were isolated using four different small EV isolation methods (differential ultracentrifugation, size-exclusion chromatography, affinity purification and precipitation) and differential centrifugation for isolation of large EVs. Western blotting, dynamic light scattering and transmission electron microscopy confirmed the enrichment of EVs. Results: Our results indicated that EVs enriched from patient blood samples contained significantly lower amounts of DNA compared to cfDNA (p &amp;lt; 0.001); &amp;gt;50-fold lower for untreated sEVs and &amp;gt;1000-fold lower for DNase-treated EVs. Thus, most of the detected vesicle-associated DNA seemed to be located outside of the vesicles. Further, tumor-derived DNA in EVs was barely detectable and the tumor-derived fraction in all evDNA samples was similar to that of cfDNA. Conclusion: Our results demonstrated that evDNA do not add any extra information compared with cfDNA as a source of tumor-derived DNA, at least not in patients with advanced pancreatic cancer. Citation Format: Morten Lapin, Kjersti Tjensvoll, Karoline Nedrebø, Eline Taksdal, Hans Janssen, Bjørnar Gilje, Oddmund Nordgard. Circulating extracellular vesicles from patients with advanced pancreatic cancer contain low levels of tumor-derived DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2287.
Abstract 6363: Short-term exposure of cancer cells to ultra-high concentrations nitric oxide induces PDL-1 upregulation
Authors: Yana Epshtein, Matan Goldshtein, Selena Chaisson, Jedidiah Monson, Matt Johnson, Amir Avniel, Steve Lisi, Hila Confino
Journal: Cancer Research (2023)

Abstract Background: We have previously shown that treating mouse colon carcinoma (CT26) tumor-bearing mice with ultra-high concentrations of nitric oxide (UNO) upregulates innate and adaptive immune cells both locally and systemically. As immune-checkpoint molecules, such as the PD-L1 receptor PD-1, are expressed on immune cells, our group assessed the potential synergy of UNO and an anti-PD-1 antibody for treating tumors in vivo. Indeed, primary tumors regressed in 53% of the CT26 tumor-bearing mice treated with UNO and anti-PD-1. Moreover, these mice were primary and distant tumor-free and survived 100 days post-treatment. In the current study, we assessed PD-L1 expression levels on cancer cells in vitro following short-term exposure to UNO. Methods: CT26 cells were exposed to 25,000 - 100,000 ppm NO for 10 - 60 seconds. The percentage of PD-L1-expressing cells was assessed by flow cytometry analysis. Results: 1. Exposing CT26 cells to 100,000 ppm NO for 10 seconds upregulated PD-L1 expression. 85.1% of cells, which are still viable or at early apoptosis, expressed PD-L1 compared to 71% of untreated cells (p&amp;lt;0.0001). Exposure of CT26 cells to 25,000 ppm or 50,000 ppm NO for 10 seconds did not change the level of PD-L1 expression significantly. 2. Exposure to 100,000 ppm NO for 30 seconds further increased the percentage of cells expressing PD-L1 to 96.7% (p&amp;lt;0.0001 compared to untreated cells). For this duration, lower concentrations of NO also increased PD-L1-expression in viable early apoptotic CT26 cells to 82.8% - 92.3% when treated with 25,000 ppm or 50,000 ppm NO, respectively. 3. Finally, a 60 second exposure of CT26 cells to 25,000 ppm, 50,000 ppm, or 100,000 ppm NO resulted in the highest percentage of PD-L1 expressing cells. Approximately 95% of all viable or early apoptotic CT26 cells express PD-L1 under all NO conditions. This finding is significant compared to 71% of cells in the control arm that express PD-L1 (p&amp;lt;0.0001). Conclusion: Short-term exposure (10 - 60 seconds) to UNO upregulates PD-L1 expression on cancer cells in an NO concentration-dependent and exposure-dependent process. A 10-second exposure to 100,000 ppm NO is sufficient to significantly induce PDL-1 expression. Therefore, NO therapy can potentially be combined with anti-PD-L1 antibody treatment to improve therapeutic outcomes. Citation Format: Yana Epshtein, Matan Goldshtein, Selena Chaisson, Jedidiah Monson, Matt Johnson, Amir Avniel, Steve Lisi, Hila Confino. Short-term exposure of cancer cells to ultra-high concentrations nitric oxide induces PDL-1 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6363.
Abstract 3264: Sotorasib, a selective G12C K-RAS inhibitor, modulates the tumor microenvironment to promote TNFα and IFNγ signaling and augment immunotherapy response
Authors: Mohammed L. Ibrahim, Dana Foresman, Hong Zheng, Eric B. Haura, Daniel Abate-Daga, Xiaoqing Yu, Amer A. Beg
Journal: Cancer Research (2023)

Abstract KRAS-G12C mutation represents a highly prevalent mutation in lung and colon carcinoma with unfavorable clinical outcome. Recently, new compounds were developed that selectively bind to K-RAS with G12C mutation. While recent clinical results demonstrate activity of these compounds, their underlying mechanisms of action and impact on the antitumor immune response are not well understood. Here, we tested G12C-Kras inhibitor (Sotorasib/AMG-510) using multiple approaches. We found that Sotorasib significantly promoted the tumor regression and the expansion of tumor infiltrating lymphocytes (TILs) in both CT26-G12C heterotopic colon cancer, and KP-G12C autochthonous GEMM lung cancer mouse models, with more profound impact when combined with anti-PD1 ICB immunotherapy. In addition, it generated a “hot” tumor microenvironment with strikingly augmented T cell effector phenotype, endorsed by enrichment of MHC-II high macrophage and reduction of suppressive myeloid cells. Interestingly, Single cell RNA sequencing of CT26-G12C tumors shows an enrichment of tumor clusters with TNFα and IFNγ as top upregulated pathways in Sotorasib-treated tumors, generating a more immune active TME. These immune active tumor clusters were conserved or further expanded upon cotreatment with anti-PD1 ICI. Conversely, immune-deficient, or Sotorasib-resistant tumors exhibited a remarkable contraction of the immune active clusters, substantiating that the immune-modulatory impact of Sotorasib relies on tumor cells adaptation and their cross talk with the tumor infiltrated lymphocytes. In vitro, Single cell RNA sequencing of CT26-G12C cells also revealed that Sotorasib and TNFα/IFNγ cytokines are affecting different tumor clusters. Moreover, further in vitro testing demonstrated that Sotorasib dramatically enhances KRAS-G12C mutant cancer cell killing by PSCA-specific CART cells. These findings provide insight into the molecular basis of G12C-Kras inhibitor-mediated immune modulation in the TME and provide insight for combinatorial regimens with checkpoint inhibitor and adoptive T cell immunotherapy to achieve optimum anti-tumor activity. Citation Format: Mohammed L. Ibrahim, Dana Foresman, Hong Zheng, Eric B. Haura, Daniel Abate-Daga, Xiaoqing Yu, Amer A. Beg. Sotorasib, a selective G12C K-RAS inhibitor, modulates the tumor microenvironment to promote TNFα and IFNγ signaling and augment immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3264.
Preliminary pharmacokinetic and safety data after a single intravenous infusion of Voyager-V1 (VV1, VSV-IFNβ-NIS) oncolytic virus in patients with relapsed refractory hematologic malignancies.
Authors: Kah Whye Peng, Adam Remick, Nabila Nora Bennani, Joselle Cook, Lianwen Zhang, Thomas E. Witzig, Javier Munoz, Stephen M Broski, Susan Michelle Geyer, Brenda F. Ginos, Luke Russell, Alice Susannah Bexon, Stephen J. Russell, Martha Lacy
Journal: Journal of Clinical Oncology (2023)

e14594 Background: Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express interferon beta (IFNβ) to boost cellular antitumor immunity and sodium iodine symporter (NIS). A phase 1 trial investigating a single infusion of VV1 in patients with relapsed refractory multiple myeloma and T-cell lymphoma (TCL) showed promising and durable clinical activity, primarily in patients with TCL. VV1 infects tumor cells and macrophages in the lymph nodes and spleen, resulting in release of tumor antigens and IFNβ that activates and boost cellular antitumor immunity. We present the preliminary pharmacokinetic analysis in patients given one intravenous (IV) dose of VV1. Methods: Patients received 5e9 to 1.7e11 TCID50 (50% tissue culture infective dose) of VV1 given over 30 minutes. We also explored the impact of infusion duration (0.25, 0.5,1 and 3 hours) in 17 patients with solid tumors. The objectives were to determine the impact of viral dose on pharmacokinetics (PK) of VSV and IFNβ. For VSV and IFNβ PK, whole blood was collected in 30 patients on days 1, 2, 3, and 8. Dose levels were 1.7E10, 5E10, and 1.7E11 TCID50. The plasma concentration-time data were estimated with non-compartmental analysis using WinNonlin 8.3. Results: The half-life of VV1 is comparable (10-12h) between dose levels of 1.7e10, 5e10 and 1.7e11. Ideal infusion rate was found to be 30 minutes and provides the highest Cmax and AUC. Most peak concentrations for viremia and IFNβ were achieved between ‘end of infusion’ and 2.5 hours, 4.5 and 24 hours, respectively. Following infusion, a second concentration peak is found in over half the patients leading to highly variable terminal elimination half-life, specifically where the second peak is at 24 hours. There was no second peak for IFNβ levels. Peak plasma concentration and systemic exposure increased in proportion to increased dose, consistent with linear clearance. Conclusions: The 30 minute infusion rate was considered the best as its PK provides the highest Cmax and AUC with no significant CRS differences among other groups. IL-6 and IFNα markers at hour 4 indicate a likely CRS and hour 24 provides a possible prediction of the grade. Cmax and AUC were also highest at 1.7e11 TCID50. This is the recommended dose that will be used in the expansion arm in patients with TCL. Clinical trial information: NCT03017820 , NCT02923466 . [Table: see text]
Abstract 2100: Genomic profiles and immune cell infiltration landscapes for lymph node metastasis in T1 lung adenocarcinoma
Authors: Fang Wu, Yue Pan, Chunhong Hu, Chen Chen, Wenliang Liu, Songqing Fan, Long Shu, Lishu Zhao, Yucheng Fu, Sujuan Zhang, Junqi Liu, Yue Zeng, Yurong Peng, Hongjing Zang, Chao Deng, Zhenhua Qiu, Fang Ma, Fenglei Yu, Xianling Liu, Lijuan Liu, Lingling Yang, Yang Shao
Journal: Cancer Research (2023)

Abstract Background: Comprehensive genomic and tumor immune microenvironment (TIME) analysis of T1 lung adenocarcinoma (LAD) may provide new insights into the biology of lymph node metastasis (LNM), thereby guiding surgical procedures and perioperative treatment. Methods: A total of 212 cases of T1 LAD were included, of which 174 cases underwent whole exome sequencing to assess gene mutation and tumor mutation burden (TMB). Tumor mutation score (TMS) was constructed from LNM identified by LASSO regression. Immunohistochemical staining was performed to assess PD-L1 levels, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) densities. Validation and supplementation were performed by RNA sequencing data from the TCGA database. Results: A total of 25 genes were associated with the risk of LNM, of which STK11, NOTCH2, RHBDF2, EGFR, and CYP2D6 could be validated by RNA sequencing. The model predicted LNM (AUC = 0.904) and 2-year recurrence and metastasis (AUC = 0.700). Besides, TILs were negatively correlated with LNM of T1 LAD, while TAMs were positively (p&amp;lt;0.05). Moreover, the TMS was correlated with the TIME, particularly TAMs(r=0.331, p&amp;lt;0.001). Conclusions: Tumor gene mutation promotes lymph node metastasis by changing the TIME, especially TAMs. Predictive models can identify high-risk patients and provide evidence for future studies of perioperative management. Citation Format: Fang Wu, Yue Pan, Chunhong Hu, Chen Chen, Wenliang Liu, Songqing Fan, Long Shu, Lishu Zhao, Yucheng Fu, Sujuan Zhang, Junqi Liu, Yue Zeng, Yurong Peng, Hongjing Zang, Chao Deng, Zhenhua Qiu, Fang Ma, Fenglei Yu, Xianling Liu, Lijuan Liu, Lingling Yang, Yang Shao. Genomic profiles and immune cell infiltration landscapes for lymph node metastasis in T1 lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2100.
Abstract 2184: Short Peptides derived from MIEN1 and their analogs exhibit anti-cancer activity in breast and prostate cancer cells
Authors: AMIT Kumar Tripathi, Jamboor K. Vishwanatha
Journal: Cancer Research (2023)

Abstract Migration and invasion enhancer 1 (MIEN1) is overexpressed in various cancers and plays an important role in cancer cell migration and invasion. Conserved regions of ITAM and prenylation motif in MIEN1 were used as a template to identify anti-cancer peptides. RNA-seq, qPCR analysis and western blots showed changes in the transcriptome and protein expression after peptide treatment. The two bioactive peptides inhibited genes and proteins responsible for cancer cell migration and invasion in both MDA-MB-231 breast cancer and DU-145 prostate cancer cells. The mechanism of the action of the peptides involves the inhibition of key pathways like Epithelial-Mesenchymal transition and Epidermal Growth Factor-mediated NF-κB pathway to exert their anti-cancer activity. Interestingly, the peptides targeted the same signal transduction pathways followed by parental MIEN1 to show its cancer properties. Thus, the two peptides acted as dominant negative effectors of MIEN1 activity. Additionally, Peptide-treatments induced apoptosis in mice groups bearing tumors derived from MDA-MB-231 cells as evidenced by increased levels of cleaved caspase-3 and PARP proteins in western blots. Interestingly, the MIEN1 mRNA and protein expression was lowered in the in vivo breast cancer tumor models which remained unchanged in MDA-MB-231 breast cancer cells indicating an improved therapeutic activity in living system. The peptides did not cause any toxicity in the mice group which received peptides only, at three times the dose used during in vivo assays. Citation Format: AMIT Kumar Tripathi, Jamboor K. Vishwanatha. Short Peptides derived from MIEN1 and their analogs exhibit anti-cancer activity in breast and prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2184.
Abstract 3091: Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068
Authors: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Hongxia Zhang, Mingchuan Guo, Ruiyu Zhou, Ye Edward Tian
Journal: Cancer Research (2023)

Abstract WEE1 is activated upon DNA damage and regulates the G2/M cell cycle checkpoints. Inhibition of WEE1, in conjunction with genetic alterations and/or a DNA damaging agent, could result in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treat cancer. Small molecule WEE1 inhibitors, such as AZD1775, showed good clinical POC (proof of concept) data in several tumors including ovarian, colon, and uterine carcinoma. We have identified a novel, potent, and highly selective WEE1 inhibitor IMP7068. Herein we will present its discovery and IND enabling in vitro and in vivo studies. IMP7068 exhibits superior WEE1/PLK1 selectivity (&amp;gt;435 fold) compared to AZD1775. IMP7068 also shows potent cytotoxicity against a wide range of cancer cell lines. In addition, IMP7068 has desirable PK profiles with long half-life and high exposure in preclinical species. Anti-tumor efficacy of IMP7068 has been demonstrated in mice CDX models of colorectal LoVo, non-small cell lung cancer NCI-H1299 and a PDX model of uterine UT5318 with good dose-response tumor inhibition and tolerability. IMP7068 is currently in a phase I study to evaluate its safety, tolerability, pharmacokinetics, and anti-tumor activity in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT04768868). Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Hongxia Zhang, Mingchuan Guo, Ruiyu Zhou, Ye Edward Tian. Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3091.
Abstract 381: Inhibition of CCR6-CCL20 axis enhances cytotoxic effect of chemotherapeutics in colon cancer
Authors: Hina Mir, Shailesh Singh
Journal: Cancer Research (2023)

Abstract Response of chemotherapeutic offered to treat colon cancer are often short-lived due to chemoresistance and severe toxicity associated with the therapy. Hence, development of less toxic treatment options is imperative to improve efficacy and therapeutic outcome. We have shown that chemokine CCR6 and its natural ligand is expressed in colon cancer and correlates with advanced disease. Aim of this study was to establish the association of CCCR6/CCL26 signaling axis on development of chemoresistance and chemotherapeutic response. Our data shows higher expression of receptor, poor cytotoxic effect of 5-Fluorouracil (5-FU) when cells are treated with CCL20 while better response to 5-FU when CCR6 signaling is blocked using anti-CCR6 monoclonal antibody. The observed differences in the cytotoxic effects of 5-FU could be primarily due to CCR6-mediated alteration of cell cycle, activation of cell survival and anti-apoptotic signaling. Further investigations in a preclinical model will rationalize developing CCR6 directed therapies to improve response to conventional chemotherapeutics and offer less toxic treatment options to colon cancer patients. Citation Format: Hina Mir, Shailesh Singh. Inhibition of CCR6-CCL20 axis enhances cytotoxic effect of chemotherapeutics in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 381.